Despite the effectiveness of triple drug combinations in anti-HIV chemotherapy, a number of critical issues remain unresolved. Existing drugs are not always effective primarily due to lack of potency, development of resistant virus, poor pharmacokinetics, lack of penetration into virus reservoirs, drug interactions affecting safety of the drug, oral bioavailability, and poor compliance by HIV infected patients. On the basis of knowledge of the molecular biology of HIV, medicinal chemistry know-how, as well as pharmacological approaches, some of these challenges can be tackled. The issues addressed in this proposal deal with viral replication in lymphatic systems, targeted drug delivery, dementia and the brain as a viral reservoir, viral resistance and latency, side effects and toxicity of drugs and drug combination, and drug interactions. During the previous funding period of this grant, these investigators developed a prodrug, (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), which is currently undergoing PhaseI/II clinical trials by Triangle Pharmaceuticals. DAPD apparently is not only an active anti-HIV agent, but it may also have a favorable viral resistant profile in vitro as well as in vivo. In order to further improve the potency, bioavailability, and selective targeted delivery to the lymphatic system and the brain, several prodrugs of DAPD are proposed. A new class of D-enantiomers of 2'-fluoro-2',3'-dideoxy-2',3'-didehydro (D4) nucleosides, including 2'-F-D4A, 2'-F-D4I and 2'-F-D4G with antiviral activity against mutant viruses including multidrug mutants has been found. However, these purine nucleosides may be limited as useful agents due to poor cellular transport. The synthesis of various prodrugs of these compounds are proposed to improve the potency as well as pharmacokinetic/pharmacodynamic profiles. The third class of compounds proposed for study are analogs of D4G because of the finding that its 6-cyclopropyl D4G has anti-HIV activity in vitro. In particular, the potential of this pro-drug to be a clinical candidate will be investigated.